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FLASH GENE
Symbol HIF1A contributors: mct/shn/pgu - updated : 09-10-2011
HGNC name hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)
HGNC id 4910
Location 14q23.2      Physical location : 62.162.118 - 62.214.977
Synonym name
  • member of PAS superfamily 1
  • member of PAS
  • ARNT interacting protein
  • ARNT-interacting protein
  • basic-helix-loop-helix-PAS protein MOP1
  • hypoxia-inducible factor 1 alpha isoform I.3
  • hypoxia-inducible factor 1-alpha
  • PAS domain-containing protein 8
  • class E basic helix-loop-helix protein 78
  • Synonym symbol(s) MOP1, HIF1, PASD8, HIF-1alpha, HIF1-ALPHA, bHLHe78
    DNA
    TYPE functioning gene
    STRUCTURE 52.86 kb     15 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map cen - D14S1429 - D14S592 - HIF1A - D14S997 - D14S290 - qter
    Physical map
    FLJ46156 14q23.1 FLJ46156 protein C14orf135 14q23.1 chromosome 14 open reading frame 135 DHRS7 14q23.1 dehydrogenase/reductase (SDR family) member 7 PSMA3P 14 proteasome (prosome, macropain) subunit, alpha type, 3 pseudogene PPM1A 14q22.3-q23.1 protein phosphatase 1A (formerly 2C), magnesium-dependent, alpha isoform RBM8B 14q22.1-q22.3 RNA binding motif protein 8B pseudogene C14orf39 14q23.1 chromosome 14 open reading frame 39 LOC390483 14 similar to sal-like 4 SIX6 14q22.3-q23 sine oculis homeobox homolog 6 (Drosophila) LOC387992 14 LOC387992 SIX1 14q22-q23 sine oculis homeobox homolog 1 (Drosophila) SIX4 14q23 sine oculis homeobox homolog 4 (Drosophila) MNAT1 14q23 menage a trois 1 (CAK assembly factor) MAD2L1P 14 MAD2 mitotic arrest deficient-like 1 (yeast) pseudogene SRMP2 14 spermidine synthase pseudogene 2 SLC38A6 14q23.1 solute carrier family 38, member 6 LOC161291 14q23.1 hypothetical protein LOC161291 PRKCH 14q22-q23 protein kinase C, eta HIF1A 14q21-q24 hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) SNAPC1 14q22 small nuclear RNA activating complex, polypeptide 1, 43kDa LOC122867 14q23.1 similar to cytochrome c oxidase subunit IV (COXIV) pseudogene (E.C. 1.9.3.1) MOCS3P 14 molybdenum cofactor synthesis 3 pseudogene SYT14L 14q23.2 synaptotagmin XIV-like LOC390484 14 similar to ATP synthase alpha subunit KCNH5 14q23.1 potassium voltage-gated channel, subfamily H (eag-related), member 5 ADPRTP2 14q24 ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase) pseudogene 2 ARHJ 14q23.1 ras homolog gene family, member J GPB5 14q23.2 glycoprotein beta 5 PPP2R5E 7p12-p11.2 protein phosphatase 2, regulatory subunit B (B56), epsilon isoform LOC390485 14 similar to ribosomal protein L31 GCATP 14q23.2 glycine C-acetyltransferase pseudogene LOC112840 14q23.2 similar to RIKEN cDNA 2600001A11 gene HSPEP2 14 heat shock 10kDa protein 1 (chaperonin 10) pseudogene 2
    RNA
    TRANSCRIPTS type messenger
    text ARE elements in the 3'UTR of mRNA
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    15 splicing 4082 92.67 826 - 2005 15750626
  • a 15 exons variant
  • encoding for the longer product
  • 14 splicing 3955 82.62 735 - 2005 15750626
  • a 14 exons variant
  • lacking exon 14
  • 15 splicing 3979 - 850 - 2005 15750626
  • lacking both exons 11 and 12
  • protein without ODD domain, TAD and C terminal NLS motif
  • exhibiting neither the activity of transactivation nor hypoxia-induced nuclear translocation
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
     vessel   moderately
    Digestiveesophagus   moderately
     mouth   highly
    Lymphoid/Immunethymus   moderately
    Reproductivemale systemtestis  moderately
    Respiratoryrespiratory tracttrachea  predominantly
    Urinarykidney   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connective   highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
     chondrocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal basic helix-loop-helix (bHLH) domain
  • a stretch of approximately 300 amino acids, termed the PAS (Per - ARNT - Sim) domain containing two internal repeats, required for heterodimerization and DNA binding
  • a MAPK-docking domain (D-domain)
  • N and C terminal hypoxia-inducible transactivation domains (TADS)
  • a transcriptional inhibitory domain
  • an oxygen-dependent degradation domain (ODD)
  • conjugated PhosphoP , Acetylated
    mono polymer homomer , dimer
    HOMOLOGY
    interspecies ortholog to Hif1a, Rattus norvegicus
    ortholog to Hif1a, Mus musculus
    ortholog to HIF1A, Pan troglodytes
    Homologene
    FAMILY
  • PAS superfamily
  • CATEGORY regulatory , transcription factor , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    text
  • shuttling of HIF1A between cytoplasm and nucleus is a complex process involving several members of the nuclear transport receptor family
  • basic FUNCTION
  • involved (essential) in cardiovascular development and systemic O2 homeostasis
  • essential for the regulation of glycolytic capacity in myeloid cells, has a role in regulation of survival and function in the inflammatory microenvironmen (
  • controlled through stability regulation of its alpha subunit, which is expressed under hypoxia but degraded under normoxia
  • regulating the expression of TWIST1 by binding directly to the hypoxia-response element (HRE) in the TWIST1 proximal promoter
  • promotes glycogen accumulation through regulating PPP1R3C expression under hypoxia, which revealed a novel metabolic adaptation of cells to hypoxia)
  • may be directly or indirectly required for normal development of the retinal vasculature, especially of the intermediate plexus (
  • HIF1A and EPAS1 play a critical role in cellular response to hypoxia
  • opposite roles of HIF1A and EPAS1 in the regulation of IL8 expression in endothelial cells
  • RUNX2, HIF1A, and VEGFA may regulate vascular angiogenesis spatially and temporally in the hypertrophic zone of the growth plate during endochondral bone formation
  • exerts a negative control over beta-cell differentiation
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS development
    PATHWAY
    metabolism carbohydrate
    signaling signal transduction
    a component
  • complexing with HIF2A and HIF2B (ARNT) for activation of genes involved in metabolism, angiogenesis, erythropo
  • esis and glycolysis through the recruitement of the CBP/p300 co-activator
  • heterodimerizing with MOP9
  • INTERACTION
    DNA
  • prostate-specific antigen gene promoter (
  • RNA
    small molecule
    protein
  • dimerize with ARNT (
  • MOP3 (
  • SRC-1 and transcription intermediary factor 2, TIF2 (
  • von Hippel-Lindau tumor suppressor protein, VHL
  • proteasome (prosome, macropain) subunit, alpha type, PSMA7 (
  • tumor suppressor TP53 (
  • Jun activation domain-binding protein-1, JAB1
  • period homolog 1 (Drosophila), PER1 (
  • functionally cooperates with c-Jun (
  • p53 binding protein homolog (mouse), MDM2 (
  • Brahma, Brm and Brahma/SWI2-related gene 1, Brg-1 (
  • SMT3 suppressor of mif two 3 homolog 1, SUMO1 (
  • cysteine-histidine-rich 1, CH1 (
  • retinoblastoma protein, pRB (
  • osteosarcoma amplified 9, endoplasmic reticulum lectin, OS9 (
  • pVHL-interacting deubiquitinating enzyme 2, VDU2 (
  • necdin homolog (mouse), NDN (
  • ARD1 (
  • MSF-A (
  • metastasis-associated protein 1, MTA1 (
  • testis specific gene antigen 10, TSGA10 (
  • beta-catenin (
  • spermidine/spermine-N(1)-acetyltransferase 2, SSAT2 (
  • RACGAP1 (HIF-1alpha function is negatively affected by its interaction with RACGAP1)
  • Nur77 (
  • signal transducer and activator of transcription3, STAT3 (
  • ELL and HIF1A are binding partners and can modulate the functions of each other in hypoxia (PMID;
  • Reptin
  • MCM2, MCM5, MCM3 and MCM7
  • via its conserved D-domain, HIF1A could serve as a platform for MAPK1 in the nucleus of the cell, thus potentially facilitating phosphorylation of other MAPK1 substrates
  • HDAC4 regulates HIF1A protein acetylation and stability, via HIF1A N-terminal lysines
  • USP19 interacts with components of the hypoxia pathway including HIF1A and rescues it from degradation independent of its catalytic activity
  • up-regulated the mRNA and protein expressions of HIF1A- and HIF1-targeted genes, and ADM up-regulated the protein expressions of HIF1A through down-regulation of PH4TM mRNA expression and PH4TM activity
  • SOCS3 is identified as a novel HIF1A target gene (HIF1A suppressed the expression of adiponectin through a SOCS3-STAT3 pathway)
  • mechanistic link between HIF1A and CDK8, two potent oncogenes, in the cellular response to hypoxia
  • ESR1 plays a crucial role in decreasing HIF1A protein levels in osteoclasts, even in hypoxic conditions (
  • positively regulates the induction of NFAT5 and HSPA4 by placental hypoxia
  • cell & other
    REGULATION
    activated by p42/p44 MAPK (
    induced by hypoxia-inducible
    inhibited by p14ARF
    MCM3 (
    valproic acid and trapoxin (
    repressed by estrogen in osteoclasts and loss of estrogen stabilizes HIF1A in those cells, which in turn activates bone resorption and promotes bone loss
    Other rapidly degraded by proteasome under normoxic conditions
    regulated by von Hippel-Lindau tumour suppressor protein, VHL (
    targeted by VALand
    pVHL-interacting protein functions as a negative regulator of HIF-1alpha transactivation (
    HIF-1&
    945; protein levels downregulated by MCM7 (
    regulated by proteasome (prosome, macropain) subunit, alpha type, 7, PSMA7 (
    PARP1 as a transcriptional coactivator of HIF-1-dependent gene expression during tumor progression (
    epigenetic regulation of CD34 and HIF1A expression during the differentiation of mast cells
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
  • cell free plasma expressions of CDKN1A and HIF1A were more prevalent in pregnancies complicated by hypoxia and/or IUGR
  • Therapy target
    SystemTypeDisorderPubmed
    diabetetype 2 
    inhibitors of HIF1A have potential utility for the treatment of type 2 diabetes
    obesity  
    inhibitors of HIF1A have potential utility for the treatment of obesity
    osteoarticularboneostéoporosis
    represents a promising therapeutic target in osteoporosis
    ANIMAL & CELL MODELS
  • Hif1a-/- mouse embryos with complete deficiency of HIF-1alpha due to homozygosity for a null allele at the Hif1a locus die at midgestation, with multiple cardiovascular malformations and mesenchymal cell death (
  • transgenic mice expressing constitutively active HIF-1alpha in epidermis displayed hypervascularity with 66% increase in dermal capillaries, a 13-fold elevation of total vascular endothelial growth factor (VEGF) expression, and a six- to ninefold induction of each VEGF isoform (
  • partialHIF-1 alpha deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia in Hif1a(+/-) mice (
  • neural cell-specific HIF-1alpha-deficient mice exhibit hydrocephalus accompanied by a reduction in neural cells and an impairment of spatial memory (
  • skeletal-muscle HIF-1alpha knockout mice have an altered exercise endurance (
  • mice lacking HIF-1alpha in their myeloid cell lineage showed decreased bactericidal activity and failed to restrict systemic spread of infection from an initial tissue focus (
  • mice lacking HIF-1alpha in osteoblasts had impaired angiogenesis and bone healing (
  • HIF-1alpha- and TWIST-null mice show similarities in their phenotypes (Yang, 2008)